The importance of the sympathetic nervous system in control of heart and blood vessels is well established. Recently a potent system that involves peptidergic modulation of sympathetic release of norepinephrine (NE) has been described. Met- and leu-enkephalin presynaptically inhibit release of NE from sympathetic nerve terminals. These peptides have been shown to be costored with NE and epinephrine in adrenal medullary chromaffin and other postganglionic sympathetic cells. They are coreleased with the catecholamines by a variety of stimuli. Thus, the eixstence of a mechanism for modulation of sympathetic release of NE at the level of the nerve terminal is firmly established. However, the role of this mechanism in any physiological or pathophysiological state in the intact organism has not been established. Although this mechanism may function in a variety of stressful situations, we propose to initially focus our investigation on its role in the hypotension associated with hemorrhage in the conscious rabbit. We have identified a paradoxical decrease in sympathetic activity during hemorrhage at the transition from normo- to hypotension. Our pilot experiments strongly suggest that adrenal medullary enkephalins may be responsible for this decrease. Our general hypothesis is that met-enkephalin released by the adrenal medulla depresses sympathetic release of NE and causes the transition to hypotension. We will test the following specific hypotheses: 1) plasma enkephalin levels rise during hemorrhage and the time course of the rise correlates with the transition to hypotension; 2) the adrenal medulla is the source of the enkephalins that produce the CV depression; 3) the enkephalins inhibit sympathetically induced peripheral vasoconstriction by a presynaptic inhibitory mechanism; and 4) the reversal by naloxone of the hypotension associated with hemorrhage is due to antagonism of peripheral rather than central opiate receptors. These studies will be performed using chronically instrumented conscious rabbits. Plasma and adrenal tissue met-enkephalin will be measured using radioimmunoassay. Plasma and adrenal catecholamines will be measured by high pressure liquid chromatography with electrochemical detection. The proposed study is an important first step in documenting the hypothetically potent role of this enkephalinergic system in modulation of sympathetic activity and thus, in cardiovascular control in the intact organism.